The sweeping 97-1 vote installs Pritzker, a longtime friend of President Barack Obama, who raised hundreds of thousands of dollars for his presidential campaigns, at the Commerce Department in time to assist in trade talks with the European Union and Pacific Rim nations.
"She knows what it takes to build companies from the ground up, and she shares my belief in doing everything we can to help businesses and workers succeed and make America a magnet for good jobs," Obama said in a statement.
Bernie Sanders, I-Vt., one of the Senate's most liberal members, was the only vote in opposition.
Pritzker becomes the fourth woman serving as secretary in Obama's current Cabinet. She is the wealthiest in the Cabinet by far, with Forbes estimating her net worth at $1.85 billion and ranking her as the 277th richest American. The commerce post has been vacant since Bryson resigned after saying he suffered a seizure that led to a series of traffic collisions.
Pritzker has led several companies and currently serves as chair of investment firms Pritzker Realty Group and Artemis Real Estate Partners. She's also on the board of the Hyatt Hotels Corp., the chain co-founded by her father. She has donated generously to education and the arts.
Pritzker won easy confirmation despite questions regarding her family's offshore trusts in the Bahamas. Obama was a critic of such tax shelters in the campaign.
"She is a force of nature," said Commerce Committee Chairman Jay Rockefeller, D-W.Va., who said the Commerce post "takes a tough person and we haven't had a tough person for a while."